Kinetic Resolution of Nitrogen Heterocycles with a Reusable Polymer‐Supported Reagent

Abstract

Shake it up baby! Simply shaking a polymer-supported reagent and the racemic amine at room temperature kinetically resolves a broad range of N-heterocycles with good selectivity. The polymer-supported reagents are robust, easy to regenerate, and can be reused dozens of times. Cleavable acyl groups can be used to give access to both amine enantiomers in a single resolution.

Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

“…8 This process offered the first catalytic method for resolving enantiomers of chiral N-heterocycles including piperazines, piperidines, morpholines, and isoquinolines. 9 …”

“…In 2011, the Bode lab reported a kinetic resolution of 2-substituted cyclic amines using a dual catalyst system consisting of an achiral NHC 3 and a chiral hydroxamide 4 (eq 1 ). 8 This process offered the first catalytic method for resolving enantiomers of chiral N-heterocycles including piperazines, piperidines, morpholines, and isoquinolines. 9 …”

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

“…10 Slightly higher reaction rates and selectivities are observed with this reagent and a recyclable, resin supported variant makes it an attractive option for practical amine resolution. 13 We first examined the kinetic resolution of the compounds in the 2,3-disubstitution series (Table 2). The data presented in Table 1 implied that substrates with a cis configuration undergo faster reaction with much higher selectivities than those observed for the trans isomers.…”

6.11 N-Acylation Reactions of Amines

“…417 Bode and coworkers have recently employed a recyclable polymer-supported acylating reagent derived from chiral hydroxamic acids for the kinetic resolution of a wide range of N-heterocycles that contain secondary amino groups in good-to-excellent ee (Figure 68(e) Figure 68 Kinetic resolution of (rac)-amines using acylating agents that contain a stereodirecting leaving group. [414][415][416][417][418] Kinetic resolution strategies involving stereoselective derivatization of a (rac)-amine with chiral acylating agents that afford diastereomeric amide products have also been developed. An impressive example of this approach involves reaction of (rac)-secondary amines with (S)-naproxen chloride, resulting in the selective N-acylation of its (S)-enantiomer to afford an (S,S)-amide in 87% de (Figure 69).…”